1. Field of the Invention
The present invention relates to 2-acetoxybenzoic acid and more particularly, the present invention relates to therapeutically useful derivatives of 2-acetoxybenzoic acid, which are substituted 1-O-(2'-acetoxy)benzoyl-.alpha.-D-2-deoxyglucopyranose derivatives.
The novel compounds of this invention exhibit analgesic, antipyretic, and antirheumatic therapeutic activity.
The compound 2-acetoxybenzoic acid is commonly known as "aspirin" and/or "acetylsalicylic acid", and is one of the most widely used compounds in the treatment of simple pain and inflammation. 2-Acetoxybenzoic acid is widely employed as an analgesic, an antipyretic, and anti-inflammatory and an antirheumatic agent, and it is particularly useful in the relief of fever, headache, myalgia, arthralgia and other pains associated with integumental structures. 2-Acetoxybenzoic acid is generally administered for these conditions in the form of powder, particle, capsule, solution, tablet or other pharmaceutically acceptable dosage form because it is advantageous from the standpoint that chronic use of the compound will not lead to a tolerance or addiction thereof. Moreover, its toxicity is much lower than most compounds possessing similar pharmacologic activity. However, 2-acetoxybenzoic acid, as used for these purposes, is well-known by the practicing skilled artisan of the medical arts to exhibit certain unwanted and deliterious side effects. Specifically, it induces occult hemorrhaging in the gastrointestinal tract, which results from contact of the insoluble solid particulate of the compound with the gastrointestinal mucosa. As a result of this insolubilization, the very acidic particles of 2-acetoxybenzoic acid will adhere to the gastrointestinal mucosa in the form of crystals and such crystals, taken together with the acidic environment of the gastrointestinal lining, will produce microetching thereof, which in turn, leads to gastrointestinal bleeding.
2. Description of the Prior Art
To date, it is known that gastric bleeding can be diminished if (1) an aqueous solution of 2-acetoxybenzoic acid is administered, or (2) a buffered aqueous solution of 2-acetoxybenzoic acid is administered. However, such solutions leave much to be desired in that they are commercially and consumerwise unacceptable, i.e., water and/or buffered solutions are unacceptable as a suitable pharmaceutical dosage form.
One product on the market, commercially known as "Alka-Seltzer.RTM." is basically an alkaline effervescent 2-acetoxybenzoic acid formulation, which does exhibit satisfactory water solubility and dissolution, insofar as 2-acetoxybenzoic acid is concerned. However, at least three disadvantages are associated with this product. Firstly, the product is contained in a tablet form and must initially be dissolved in water prior to consumption. Secondly, because the product contains a high amount of sodium ion, it is unacceptable for administration to hypertensive patients (those who suffer from high blood pressure), because it has now been medically established that the sodium ion contributes to hypertension. Thirdly, the alkaline nature of the product per se alters the pH of the blood and urine to the alkaline side. Chronic use of this product could thus initiate alkalosis.
It has also been proposed to avoid the adverse effects of 2-acetoxybenzoic acid by the use of various esterified derivatives thereof, wherein transient blocking of the acidic carboxylic group of aspirin occurs. For instance, French Patent No. M1453 describes various antipyretic and analgesic compounds formed by esterifying 2-acetoxybenzoic acid with various sugars. Whether such derivates are viable substitutes for 2-acetoxybenzoic acid depends not only upon whether these derivatives have therapeutic value per se, but to a larger extent upon whether these derivatives have the potential to revert to 2-acetoxybenzoic acid by hydrolysis in vivo.
In this respect, it is notable that certain derivatives of 2-acetoxybenzoic acid tend to hydrolyze so as to form the corresponding ester of salicylic acid and not aspirin. The following reaction scheme serves to illustrate the manner in which derivatives of 2-acetoxybenzoic acid may hydrolyze: ##STR1##
It is apparent that only those esterified derivatives of 2-acetoxybenzoic acid which hydrolyze according to reaction scheme (I), so as to produce aspirin, are viable substitutes for aspirin. Also, such a substitute must hydrolyze at a rate sufficient to release aspirin in therapeutically effective quantities.
It has recently been discovered that the aspirin derivative, 1-O-(2'-acetoxy)benzoyl-.alpha.-D-glucopyranose, tends to hydrolyze so as to form the corresponding sugar derivative of salicylic acid, as per reaction scheme (II) depicted above. Furthermore, to the extent that hydrolysis to aspirin takes place, such hydrolysis takes place only at a very slow rate. Cf. the aforenoted Hussain et al application, Ser. No. 043,814.
In summary, the various prior art sugar derivatives of 2-acetoxybenzoic acid present a non-irritating neutral molecule to the gastrointestinal lining when administered for therapeutic purposes. However, the group which blocks the carboxylic acid function of 2-acetoxybenzoic acid tends to be bound thereto very tightly. Such prior art derivatives, therefore, do not release aspirin in vivo in therapeutically sufficient quantities. Thus, a need exists for a 2-acetoxybenzoic acid derivative, wherein transient blocking of the carboxylic function occurs, yet wherein the blocking group is not so tenaciously bound thereto.